ORGANIC LETTERS
CuBr-Catalyzed Coupling of N-Tosylhydrazones and Terminal Alkynes: Synthesis of Benzofurans and Indoles
2011 Vol. 13, No. 5 968–971
Lei Zhou, Yi Shi, Qing Xiao, Yizhou Liu, Fei Ye, Yan Zhang, and Jianbo Wang* Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
[email protected] Received December 12, 2010
ABSTRACT
A new method for the synthesis of benzofurans or indoles via ligand-free CuBr-catalyzed coupling/cyclization of terminal alkynes with N-tosylhydrazones derived from o-hydroxy- or o-aminobenzaldehydes has been developed. A wide range of functional groups were found that are able to tolerate the reaction conditions.
Benzofuran and indole moieties are common structural units in natural products and exhibit interesting biological activities and potential pharmaceutical applications.1 Among the methods to construct such structures, Pd-based crosscoupling reactions of o-iodophenols or o-iodoaniline with terminal alkynes with copper iodide as a cocatalyst (Sonagashira coupling), followed by 5-endodig cyclization, have been studied extensively in recent years.2,3 However, a major drawback of this process for large-scale synthesis is the use of two metal catalysts, making recovery of the expensive palladium difficult. Compared to noble-metal catalysts, copper-based methods have obvious economic attractiveness. Recently, several highly efficient copper-based Sonogashira coupling/cyclization (1) For selected reviews, see: (a) Cagniant, P.; Cagniant, D. Adv. Heterocycl. Chem. 1975, 18, 343. (b) Donnelly, D. M. X.; Meegan, M. J. In Comprehensive Heterocyclic Chemistry, Vol. 4; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; pp 657-712. (c) Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, U.K., 1996; Vol. 2, p 395. (d) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, U.K., 1996; Vol. 2, p 207. (e) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2007, 24, 843. 10.1021/ol103009n r 2011 American Chemical Society Published on Web 01/26/2011
sequences have emerged for the synthesis of furans and indoles.4 For example, Venkataraman and co-workers have recently reported a protocol for the synthesis of benzofurans from o-iodophenols and terminal alkynes catalyzed by a well-defined [Cu(phen)(Ph3P)2]NO3 catalyst.4b The synthesis of 2-substituted indoles was developed by Ma (2) For reviews on Pd/Cu-catalyzed coupling and cyclization reactions, see: (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (c) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (e) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (f) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (3) For recent examples, see: (a) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem. Soc., Chem. Commun. 1992, 41. (b) Kundu, N. G.; Pal, M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1 1997, 2815. (c) Khan, M. W.; Alam, M. J.; Rashid, M. A.; Chowdhury, R. Bioorg. Med. Chem. 2005, 13, 4796. (d) Sakai, H.; Tsutsumi, K.; Morimoto, T.; Kakiuchi, K. Adv. Synth. Catal. 2008, 350, 2498. (e) Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.; Maryanoff, B. E. Org. Lett. 2000, 2, 89. (f) Djakovitch, L.; Rollet, P. Adv. Synth. Catal. 2004, 346, 1782. (g) Leogane, O.; Lebel, H. Angew. Chem., Int. Ed. 2008, 47, 350. (h) Pal, M.; Subramanian, V.; Yeleswarapu, K. R. Tetrahedron Lett. 2003, 44, 8221. (i) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017. (j) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307. (k) Palimkar, S. S.; Kumar, P. H.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron 2006, 62, 5109. (l) Pal, M.; Subramanian, V.; Batchu, V. R.; Dager, I. Synlett 2004, 11, 1965. (m) Bochicchio, A.; Chiummiento, L.; Funicello, M.; Lopardo, M. T.; Lupattelli, P. Tetrahedron Lett. 2010, 51, 2824.
and co-workers using a CuI/L-proline system.4f We noted, however, in these cases ligands were essential for the success of the reactions. Considering the importance of benzofurans and indoles, it is highly desirable to develop alternative and novel methods for the synthesis of these structures. In the past few years, N-tosylhydrazones have been proven as a new type of coupling partner for Pd-catalyzed crosscoupling reactions.5 Moreover, palladium-based threecomponent coupling of N-tosylhydrazone, aryl bromide, and terminal alkyne with copper iodide as a cocatalyst has been reported by our group.6 More recently, we have developed a method for the synthesis of substituted allenes via Cu(I)-catalyzed coupling of N-tosylhydrazones with terminal alkynes.7 In this case, a bisoxazoline ligand was crucial for efficient allene formation. The mechanism for the allene formation is proposed as shown in Scheme 1. Cu carbene intermediate A is formed through dediazotization of the in situ generated diazo substrate. Subsequently, the alkynyl group of the Cu carbene A goes through a migratory insertion into the carbenic carbon to form intermediate B, which is followed by protonation to afford the allene product. We have conceived that if a suitable intramolecular nucleophile is introduced, the initially formed allene or intermediate B may undergo a cyclization to afford benzofuran or indole if the nucleophile is a hydroxy or an amino group, as shown by the transformation from B to D to E.8 Herein we wish to report a method for the synthesis of benzofurans and indoles from N-tosylhydrazones derived from o-hydroxy- or o-aminobenzaldehydes and terminal alkynes based on a ligand-free CuBr-catalyzed couplingallenylation-cyclization sequence. Initially, the reaction conditions were optimized starting from N-tosylhydrazone 1a and phenylacetylene (2a) in 1, 4-dioxane at 100 °C with various copper catalysts, as summarized in Table 1. It was observed that CuBr gave the best result (Table 1, entries 1-5). Cu(OAc)2 and CuBr2 were also effective, albeit affording the products with slightly (4) (a) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58 (16), 4716. (b) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4, 4727. (c) Saejueng, P.; Bates, C. G.; Venkataraman, D. Synthesis 2005, 1706. (d) Li, J. H.; Li, J. L.; Wang, D. P.; Pi, S. F.; Xie, Y. X.; Zhang, M. B.; Hu, X. C. J. Org. Chem. 2007, 72, 2053. (e) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, M.-B.; Hu, X.-C. J. Org. Chem. 2007, 72, 2053. (f) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844. (g) Wu, M.; Mao, J.; Guo, J.; Ji, S. Eur. J. Org. Chem. 2008, 4050. (h) Jaseer, E. A.; Prasad, D. J. C.; Sekar, G. Tetrahedron 2010, 66, 2077. (5) (a) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 5587. (b) Barluenga, J.; Tomas-Gamasa, M.; Moriel, P.; Aznar, F.; Valdes, C. Chem.-Eur. J. 2008, 14, 4792. (c) Barluenga, J.; Escribano, M.; Moriel, P.; Aznar, F.; Valdes, C. Chem.-Eur. J. 2009, 15, 3291. (d) Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun. 2010, 1724. (e) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2009, 11, 4732. (6) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2010, 132, 13591. (7) Xiao, Q.; Xia, Y.; Li, H.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2011, 50, online, DOI: 10.1002/anie.201005741. (8) For examples of ring-closing reaction of allenes, see: (a) Mukai, C.; Yamashita, H.; Kitagaki, S. Org. Lett. 2001, 3, 3385. (b) Mukai, C.; Ohta, M.; Yamashita, H.; Kitagaki, S. J. Org. Chem. 2004, 69, 6867. (c) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J. Am. Chem. Soc. 2004, 126, 8744. (d) Yu, X.; Seo, S.-Y.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 7244. (e) Kitagaki, S.; Kawamura, T.; Shibata, D.; Mukai, C. Tetrahedron 2008, 64, 11086. (f) Inuki, S.; Yoshimitsu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2009, 11, 4478. Org. Lett., Vol. 13, No. 5, 2011
Scheme 1. Cu-Catalyzed Coupling of N-Tosylhydrazone and Terminal Alkyne
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
base
solvent
yield%b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19c
CuI CuBr CuCl CuOTf Cu(MeCN)4PF6 Cu(OAc)2 CuBr2 FeCl2 AgOTf AuCl3 none CuBr CuBr CuBr CuBr CuBr CuBr CuBr CuBr
Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 t BuOK NaOMe Cs2CO3
dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane MeCN DMF DCE toluene MeCN MeCN MeCN MeCN
74 82 63 69 68 58 55 0 trace 7 0 90 77 70 10 48 51 11 45
a
All the reactions were carried out in sealed tubes using 0.4 mmol of tosylhydrazone 1a, 0.5 mmol of phenylacetylene, 10 mol % of catalyst, and 3 equiv of base in the solvent at 100 °C for 4 h. b Yields were determined by GC using dodecane as internal standard. c The reaction was carried out at 80 °C.
diminished yields (entries 6 and 7). Other catalysts such as FeCl2, AgOTf, and AuCl3 were found to be essentially 969
Table 2. Reaction of N-Tosylhydrazone 1a with Various Terminal Alkynes Catalyzed by CuBra,8
Table 3. CuBr-Catalyzed Reaction of N-Tosylhydrazone with 1-Alkynesa,8
a
Reaction conditions: N-tosylhydrazone 1 (0.4 mmol), 1-alkyne 2 (0.5 mmol), CuBr (10 mol %), Cs2CO3 (1.2 mmol), MeCN (5 mL), 100 °C, 4 h. b Isolated yield.
a Reaction conditions: N-tosylhydrazone 1a (0.4 mmol), alkyne 2 (0.5 mmol), CuBr (10 mol %), Cs2CO3 (1.2 mmol), MeCN (5 mL), 100 °C, b 4 h. Isolated yield. c 31% yield of alkyne was recovered.
ineffective in this reactions (entries 8-10). A control experiment showed that no product could be detected in the absence of a copper catalyst (entry 11). Further inspection of the reaction conditions revealed that this reaction proceeded more efficiently in polar solvents such as MeCN, DMF, and 1,2-dichloroethane (DCE) 970
(entries 12-14), whereas nonpolar solvent toluene was found to be unfavorable (entry 15). Then, a series of bases such as K2CO3, tBuOLi, and NaOMe were examined; however, they were all less efficient compared with Cs2CO3 (entries 16-18). Finally, we found that the yield of 3a decreased sharply when the reaction was carried out at lower temperature (entry 19). Having optimized the reaction conditions, we then explored the scope and limitation of the present CuBr-catalyzed tandem coupling-allenylation-cyclization method with a variety of terminal alkynes and N-tosylhydrazones.9 As shown in Table 2, various functional groups including the Org. Lett., Vol. 13, No. 5, 2011
aryl, alkyl, naphthyl, and heterocycle present in alkynes 2 were tolerant of the reaction conditions. The reaction was found to be not significantly affected by the substituents on the aromatic ring of the terminal alkyne; both electron-rich (entries 2-3 and 6-7) and electron-deficient aryl substituted alkynes (entries 4 and 5) were effective. Treatment of 3-thienylacetylene with N-tosylhydrazone 1a furnished the benzofuran 3h in a yield of 91% (entry 8). Naphthyl and alkyl alkynes were also suitable for the reactions, albeit generating the corresponding products with moderately high yields (entries 7 and 9-10). We were pleased to find that the alkyne bearing a hydroxyl group reacted with N-tosylhydrazone 1a under the optimized conditions to afford the desired benzofuran in 64% yield without the need of functional group protection (entry11). To further expand the scope of the reaction, various substituted salicyl N-tosylhydrazones were employed as substrates to react with phenylacetylene. As shown in Table 3, hydrazones with a methoxy group at the meta- or paraposition were both effective, affording the corresponding benzofurans 3l and 3m in yields of 79% and 72% respectively (entries 1 and 2). In another case, coupling of phenylacetylene with hydrazone bearing a naphthyl group (1d) led to the product 3n in 53% yield (entry 3). It is noteworthy that a bromo substituent could survive in the reaction of 1e and phenylacetylene (entry 4). Further examination of the scope of N-tosylhydrazone showed that the strong electronwithdrawing group on the aromatic ring hampered the (9) General procedure CuBr-catalyzed reaction of N-tosylhydrazone and alkyne: CuBr (5.8 mg, 10 mol%), Cs2CO3 (1.2 mmol, 390 mg), and N-tosylhydrazone 1a-h (0.4 mmol) were suspended in MeCN (5 mL) in a 10 mL Schlenk tube under nitrogen. Then terminal alkynes 2 (0.5 mmol) were added. The resulting solution was stirred at 100 °C for 4 h. After cooling to room temperature, the resulting mixture was filtered through a short path of silica gel, eluting with hexane and CH2Cl2. The volatile compounds were removed in vacuo, and the residue was purified by column chromatography (SiO2, hexane).
Org. Lett., Vol. 13, No. 5, 2011
formation of benzofurans. When N-tosylhydrazone 1f was employed, the reaction with phenylacetylene yielded the benzofuran 3p in only 48% (entry 5). Next, we checked the possibility of assembling 2-substituted indoles by our process and were pleased to observe that reaction of N-tosylhydrazone 1g with phenylacetylene, 3-thienylacetylene, and 4-phenyl-1-butyne delivered the corresponding indole 3q-s in yields of 74%, 72%, and 41% respectively (entries 6-8). As an additional example, it was found that using Ac protected N-tosylhydrazone 1h also afforded the desired product in 38% yield (entry 9). In summary, we have developed a new method for the synthesis of benzofuran and indole via CuBr-catalyzed coupling/allenylation/cyclization of terminal alkynes with N-tosylhydrazone derivatives. This method is based on salicyl N-tosylhydrazones, which are easily available from the coressponding aldehydes. A wide range of functional groups were found that are able to tolerate the reaction conditions. Moreover, this reaction uses inexpensive CuBr as a catalyst and is ligand-free, thus offering significant economic advantages over the many previous methods. Further application of this method is currently under investigation in our laboratory, and the results will be reported in due course. Acknowledgment. Financial support from the National Natural Science Foundation of China (Grant Nos. 20902005, 20832002, 210722009, 20821062), 973 Program (No. 2009CB825300), GSK R&D China and China Postdoctoral Science Foundation is gratefully acknowledged. Supporting Information Available. Procedures for synthesis and characterization of products (1H and 13C NMR data). This material is available free of charge via the Internet at http://pubs.acs.org.
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